Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma

Abstract

Background/aimsMicrophthalmia, anophthalmia and coloboma (MAC) are clinically and genetically heterogenous rare developmental eye conditions, which contribute to a significant proportion of childhood blindness worldwide. Clear understanding of MAC aetiology and comorbidities is essential to providing patients with appropriate care. However, current management is unstandardised and molecular diagnostic rates remain low, particularly in those with unilateral presentation. To further understanding of clinical and genetic management of patients with MAC, we charted their real-world experience to ascertain optimal management pathways and yield from molecular analysis.MethodsA prospective cohort study of consecutive patients with MAC referred to the ocular genetics service at Moorfields Eye Hospital between 2017–2020.ResultsClinical analysis of 50 MAC patients (15 microphthalmia; 2 anophthalmia; 11 coloboma; and 22 mixed) from 44 unrelated families found 44% had additional ocular features (complex) and 34% had systemic involvement, most frequently intellectual/developmental delay (8/17). Molecular analysis of 39 families using targeted gene panels, whole genome sequencing and microarray comparative genomic hybridisation identified genetic causes in, 28% including novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3), and a molecular diagnostic rate of 33% for both bilateral and unilateral cohorts. New phenotypic associations were found for FOXE3 (bilateral sensorineural hearing loss) and MAB21L2 (unilateral microphthalmia).ConclusionThis study highlights the importance of thorough clinical and molecular phenotyping of MAC patients to provide appropriate multidisciplinary care. Routine genetic testing for both unilateral and bilateral cases in the clinic may increase diagnostic rates in the future, helping elucidate genotype–phenotype correlations and informing genetic counselling.

A Natural History Study of RP2-Related Retinopathy

“…Patients with molecular genetic confirmation of disease-causing variants of RP2 were identified. The pathway of genetic testing and variant interpretation at Moorfields has been previously described extensively [ 6 , 27 , 28 ]. Referred patients presenting clinical findings suggestive of genetic eye diseases are offered genetic testing of either single gene, targeted gene panels, or whole genome sequencing.…”

Structural Variant Disrupting the Expression of the Remote FOXC1 Gene in a Patient with Syndromic Complex Microphthalmia

“…Indeed, the number of OM individuals lacking a genetic diagnosis stays largely unchanged after the analysis of the main known genes by Targeted- or Whole-Exome Sequencing. The identification of new genes in OMs is actually rare, typically occurring within isolated families [ 5 ]. In other words, it seems possible that most of the main genes involved in OMs have already been discovered and that the mechanisms or lesions responsible, in particular those affecting the expression regulation of these genes, remain to be identified.…”

Identification of Novel Coloboma Candidate Genes through Conserved Gene Expression Analyses across Four Vertebrate Species

“…The use of next-generation sequencing, including targeted gene panels and whole genome sequencing, in MAC patients and their families has led to an increase in genetic diagnosis rates of up to 33% [20], with MAC panels now including up to 86 different genes [21]. However, very few OC loci show recurrence among unrelated families, and recent studies suggest that over 80% of cases do not have a genetic diagnosis [7,22,23].…”